UNSATURATED SUGARS IN NUCLEOSIDE SYNTHESES (103 mg), and pyrrolidine (110 mg) was heated under reflux in a Soxhlet extraction apparatus containing molecular sieves (5.4) for 2 days. The cooled reaction mixture was stirred for 20 min in 5% sulfuric acid, after which the layers were separated and the benzene layer was extracted twice with 20-ml portions of 57, sulfuric acid. The sulfuric acid solution was basified and extracted with methylene chloride. The methylene chloride was evaporated and the residue was subjected to preparative tlc (silica gel, 107, methanol-chloroform) to yield 28 mg (19%) of ketone 11 identical in all respects with the material obtained above. The other materials from preparative tlc showed no maxima at 174.5cm-l in their infrared spectra. Deuterium Exchange of Ketone 11.-A solution of the tetracyclic ketone 11 (12.0 mg, 0.045 mniol) in 1: 1 deuterium oxidedioxane (0.5 ml) containing a small amount of anhydrous potassium carbonate was heated a t 80” (oil bath) for 5 hr. Additional deuterium oxide was added (0.25ml) and the solution was allowed to stand at room temperature for 24 hr. The solution was extracted with dry methylene chloride and the organic phase was washed with a small volume of deuterium oxide. The organic solution was concentrated under reduced pressure and the residue was dried under high vacuum for 12 hr to give the deuterated ketone (11.6 mg, 95%) as a colorless, crystalline solid. The pmr spectrum showed a disappearance of the AB quartet assigned to the methylene protons of C-1 in the protio compound. The mass spectrum showed m/e 289,244,and 228.
J . Org. Chem., Vol. 37, N o . 23,1972 3695 11,12-Methylenedioxy-2,3,3a,4,5,6,8,9-octahydro-lH-benzosolution of ketone 11 (18 mg), 1,3-propanedithiol (180 mg), and p-toluenesulfonic acid hydrate (25mg) in benzene (15 ml) was placed in a Soxhlet extractor containing molecular sieve (SA)and heated under reflux for 4.5 hr. The reaction mixture was extracted with 5% sulfuric acid and the aqueous extracts were basified and extracted with methylene chloride to yield the crude thioketal, which showed no carbonyl absorption in its infrared spectrum. The crude thioketal was dissolved in 10 ml of 95% ethanol and heated under reflux overnight with ca. 100 mg of Raney nickel. The reaction mixture was filtered, concentrated, and subjected to preparative tlc (570 methanol-chloroform on silica gel) to afford 10 mg of the title compound. The mass spectrum of this material was identical with that of an authentic sample8 obtained from the hydrochloride in the usual manner. The picrates8 of the two samples were identical by melting point behavior and their pmr spectra were identical. [a]cyclopenta[i]quinolizine.-A
Registry No.-1, 35667-11-9; 2, 35667-12-0; 3, 35667-13-1; 4, 35667-14-2; 4 (HCl), 35667-15-3; 5 , 35667-16-4; 6, 35667-17-5; 7, 35667-18-6; 7 (HCl), 35667-19-7; 10,35667-20-0; 11,35667-21-1.
The Direct Utilization of Unsaturated Sugars in Nucleoside Syntheses. The Synthesis, Configuration, and Conformation of Certain Hex-l-enitol-3-yl-, Hex-2-enopyranosyl-, and Hexopyranosylpurines. The Preparation of 9-(1,5-~4nhydro-2,3-dideoxy-~-arabino-hex-l-enitol-3-yl)adenine and 9-(2,3-Dideoxy-~-~-erylhro-hex-2-enopyranosyl)adenine from D-Glucal’ ELDOX E. LEUTZINGER,~ TAKASHI MEGURO, AND LEROY B. TOWNSEND Department of Chemistry and Department of Biopharmaceutical Sciences, University of Utah, Salt Lake City, Utah 84111
DENNISA. SHEMAN,* MARTINP. SCHWEIZER, CHARLES 11. STEWART, AND ROLAND K. ROBINS I C N Kucleic Acid Research Institute, Irvine, California
98664
Received December B l , 1971 The acid-catalyzed fusion of 3,4,6-tri-O-acetyl-n-g1ucal (I) and 2-acetamido-6-chloropurine has furnished the 01 and p anomers of 2-acetamido-6-chloro-9-(4,6-di-O-acetyl-2,3-dideoxy-~-erythro-hex-2-enopyranosyl)-9H-purine (111) and 2-acetamido-6-chloro-9-(1,5-anhydro-2,3-dideoxy-~-arab~no-hex-l-enitol-3-yl)-9H-purine (IX). A facile conversion of I11 to 2-amino-9-(2,3-dideoxy-~-erythro-hex-2-enopyranosyl)-9H-purine-6-thiol (VI) and 9-(2,3-dideoxy-~-erythro-hex-2-enopyranos~l)guanine(VII) was effected by the appropriate functional group transformation. Cis dihydroxylation of VI1 furnished the 2’,3’-dihydroxyhexopyranoside,which hydrolyzed to give n-mannose, n-allose, and guanine and firmly established the position of the endocyclic double bond of I11 as C-2’4-3’. The direct fusion of I with either 6-chloro-2-methylthiopurine or 6-benzamidopurine furnished a mixture of the corresponding diastereoisomeric 9-( 1,5-anhydro-2,3-dideoxy-~-erythro-hex-l-enitol-3-yl)-9H-purines and 9-(2,3-dideoxy-n-erythro-2-enopyranosyl)-9H-pur~nes.The conformation and anomeric configuration of these nucleosides was assigned with the aid of pmr spectroscopy. 9-(2,3-Dideoxy-p-~-erythro-hexopyranosyl)adenine ( X X I I I ) and 9-( 1,5-anhydro-2,3-dideoxy-~-arabino-hexitol-3-yl)adenine ( X X I I ) were obtained by hydrogenation of X I X and XX, respectively. Compound XXIII has a 2’,3’-dideoxypyranosyl structure similar to that found in amicetin.
The direct utilization of glycals in the “acid-catalyaed” fusion reaction has been the subject of prelimi~ ~ and nary reports from our l a b o r a t ~ r i e sas~ ~a ~new general synthetic approach to the preparation of 2’,3’unsaturated pyranosyl nucleosides structurally related (1) This research was supported in p a r t by Research Contract fPH43-651041 with the Chemotherapy National Cancer Institutes, National Institutes of Health, Public Health Service. ( 2 ) I n partial fulfillment of the requirements for the P h . D . Thesis, Eldon E. Leutzinger, University of Utah, 1971. (3) W. A. Bowles and R . K. Robins, J . Amer. Chem. Soc., 86, 1252 (1964). (4) E. E. Leutzinger, R . K. Robins, and L. B . Townsend, Tetrahedron Lett., 4475 (1968). (5) E . E . Leuteingnr, R . K. Robins, and L. B. Townsend, i b i d . , 3751 (1970).
to Blasticidin Sa6 The structural elucidation7~* of Blasticidin S has established this nucleoside antibiotic t o be a pyranosyl derivative of cytosine possessing an endocyclic double bond in the 2,3 position of thc carbohydrate moiety. Blavticidin S has been shown t o inhibit several transplantable animal tumorsg and t o inhibit protein synthesis. lo (6) S. Takeuchi, K . Hirayama, K. Ueda, H. Sakai, and H. Yonehara, J . Antibzot. (Tokyo), 11A,l ( 1 9 5 8 ) . (7) J. J. Fox and K. A. Watanabe, Tetrahedron Lett., 897 (1966); K . A. Watanabe, I. Wempen, and J. J. Fox, Chem. Pharm. Bull., 18, 2368 (1970). (8) H. Yonehara and N. Otake, Tetrahedron Lett., 3785 (1966). (9) 3’. Tanrtka, Y . Sakagami, H. Yamaki, and H . Umeeawa, J. Antzbzot. (Tokyo), 14A, 123 (1961). (10) H. Yamaguchi and N, Tanaka, J . Biochen., 60, 632 (1966).
3696 J . Org. Chem., Vol. 37, No. 223, 1972
SHUMAN, et al.
c1
I
+ AcN
I
\
I11
AcNH
IX
Va C1
IV
V
Another nucleoside antibiotic, amicetin, l1,I2 has been A mixture of 3,4,6-tri-0-acetyl-~-glucal (I) and 2shown to possess a 2,3-dideoxypyranose moiety attached acetamido-6-chloropurine (11) was fused in the presdirectly t o the heterocyclic base, cytosine. Since ence of a catalytic amount of p-toluenesulfonic acid at amicetin has likewise shown biological activity as a 120" for 2 hr under vacuum. Preparative t,hiclc layer selective inhibitor of protein synthesis, l 2 it seemed chromatography separated the nucleosidic mixture worthwhile to investigate the synthesis of similar 2',3'into two nucleoside types, I11 and I X . Nucleoside I11 unsaturated and 2',3 '-dideoxypyranosyl nucleosides of was assigned the st'ructure 2-acetamido-6-chloro-9-(4,6purine bases. The use of u-glucal for syntheses of di-0-acetyl-2,3-dideoxy-~-erythro-hex-2-enopyranosyl)9H-purine. nucleosides of this type was first reported by Bowles and Robins3 in 1964. It was discovered during the The absorption peaks in the 6 6.1-6.3 region of the pmr spectrum of I11 were assigned to H-2' and H-3' of a 2 ' > course of these studies that fusion of the requisite 3'-unsaturated pyranosyl nucleoside derivative by compurine base with D-glucal gave in addition t o the desired parison wit'h similar absorption patterns observed pre2',3'-unsaturated nucleoside also a 1',2'-unsaturated v i o u ~ l yfor~ ~certain ~ ~ ~ 2,3-dideoxy-~-e~ythro-hex-2~ ~ pyranosyl nucleoside with purine attachment at enosides. The signals at 6 2.05-2.15 were assigned to position 3 of the pyranose ring. A preliminary report of this interesting observation has been reported from the acetyl groups at C-4' and C-6' of the carbohydrate. The presence of only two acetyl groups for the carboOUI first report,6 Ferrier, et a1.,l3 our l a b ~ r a t o r y .Since ~ and Iiondo, et al.,I4 have recently noted the isolation hydrate moiety of I11 indicated that loss of one acetoxy group17 from 3,4,6-tri-0-acetyl-~-glucal (I) had ocof thc 3'-dcoxyglycal nucleosides of 2,6-dichloropurine and uracil. The present work describes the charcurred and was accompanied by a rearrangement of the 1,2 endocyclic double bond to the 2,3 position acterization of the various nucleoside products obtained during nucleoside formation. This type of rearrangefrom our studies in this area. I n particular, 3,4,6-triment wit'h glycals has also been observed in the reac0-acetyl- D-glucal and 6-benzamidopurine gave an tions of certain phenols16j1gwith 3,4,6-tri-0-acetyl-nexcellent yield (total 76YC) of the four isomeric nucleoglucal to furnish the corresponding 4,6-di-O-acet,yl-2,3sides, XVIII, XIX, XX, and XXI. The 9-(1,5dideoxy-~-erythro-hex-2-enopyranosides. anhydro-2,3-dideoxy-u-arabino(or ribo-) hex-l-enitolThat nucleoside I11 was in fact an anomeric mixture 3-yl)-SH-purines represent a type of nucleoside which was obtained from the pmr spectrum in deuteriochloroshould be resistant to enzymatic degradation and chemform, which showed two sets of resonances for the ical hydrolysis. It should be noted that the presence -KH of the 2-acet'amido group, the H-8 prot>onand the of a doublc bond at the 2',3' position such as in Blasvinyl protons. The separation and anomeric assignticidin S or in 9- (2,3-dideoxy-fi-~-erythl'o-hex-2-enopyranosy1)adenine (XIX) and similarly at the 1',2' poment is presented later. sition as in 9-( l15-anhydro-2,3-dideoxy-~-a~abino-hex-l-Treatment of the anomeric mixture 111wit'h a methanolic solution of sodium hydrosulfide resulted in a cnitol-3-yl) adenine (XX), gives the pyranose ring facile nucleophilic displacement, of the 6-chloro group rigidity and conformation not totally unlike the furwith a concomitant removal of the acetyl blocking anose ring of the naturally occurring nucleosides. The groups to furnish a 41Yc yield of 2-amino-9-(2,3-diimportance of this obscrvation will be determined by deoxy-~-erythro-hex-2-enopyranosyl)-9H-purine-6-thiol further rescarch in various biological systems. (VI), A comparison of the ultraviolet absorption (11) For a review of t h e chemistry and biochemistry of amicetin, see R . J. Suiiadolnik, "Xucleoside Antibiotics," Wiley-Interscience, S e w York, N. Y . , 1970, p 203. (12) 4.Bloch and C. Coutsogeorgopoulos, Biochemistrg, 6, 3345 (1966). (13) R. J. Ferrier and R.1. M. Ponipom, J. Chem. SOC.C , 553 (1971). (14) T.Kondo, H . n'akai, and T. Goto, Agr. B i d . Chem., 36, 1970 (1971).
(15) (16) (17) (18) (19)
D. M. Ciment and R . J. Ferrier, J. Chem. Soc., 441 (1966). R . J. Ferrier, W. G. Overend, and G . H. Sankey, ibid., 2830 (1965). Presumed to be the C-8' acetoxy group.18 See R. J. Ferrier, ibid., 5443 (1964). R. J. Ferrier, W. G. Overend, and A . E , Ryan, i b i d . , 3667 (1962).
J . Org. Chem., Vol. 37, No. 23, 1972 3697
USSATURATED SUQARS IN NUCLEOSIDE SYKTHESES spectrum of V I with the iiv spectra of l-methyl-,20 3-methyl-,21 7-methyl-,z2and 9-methyl-2-amin0-6-thiopurine23established X-9 as the site of glycosylation for VI, and consequently for I11 and IX. SH
I
VI
n
0
D-allose HO VI1
OH OH VIII
Treatment of VI with hydrogen peroxide in a 20% aqueous ammonia solution effected a smooth conversion of the sulfur atom at position six to an oxygen atom and afforded a 78% yield of 9-(2,3-dideoxy-~erythro-hex-2-enopyranosy1)guanine(VII). The pmr spectrum of VI1 revealed a retention of the absorption peaks assigned to the olefinic protons (H-2’ and H-3’, 6 6.0-6.35, multiplet) and established that the oxidation step had occurred without effect a t the 2’,3’ endocyclic double bond. The endocyclic double bond of the carbohydrate moiety for the above nucleosides was tentatively assigned to the 2’,3’ positions; however, this double bond could theoretically be located in one of several possible positions, 1’)2’ (A), 2’,3’ (B), and3’,4’ (C). Structure CH20R
A
B
C
R = H , Ac
A was eliminated on the basis of the significant differences observed in the pattern of absorption peaks assigned t o the carbohydrate moiety in the pmr spectra of 1 and 111. Elimination of structure C was possible on the basis of the following ptudy. Treatment of 9- (2,3-dideoxy-~-erythro-hex-2-enopyran osy1)guanine (VII) with 30yo hydrogen peroxide containing a catalytic amount of osmium tetroxide furnished a cis glycol derivative which was subsequently assigned structure VIII. The stereospecific mode of addition (20) C. W. Noell, D. W.Smith, and R. K. Robins, J. Med. Pharm. Chem., 6, 996 (1962). (21) L. 0.Townsend and R. K . Robins, J. Amer. Chem. Soc., 84, 3008 (1962). (22) K . N. Prasad and R . K. Robins, i b i d . , 79, 6401 (1957). (23) C . W . Noell and R . K. Robins, J . M e d . Pharm. Chem., 6, 568 (1962).
for osmium tetroxide should furnish a nucleoside with the carbohydrate moiety in the manno and/or all0 configuration. The hydrogen peroxide-osmium tetroxide reagent has been reportedz4to effect a facile conversion of an ethyl 2,3-dideoxy-~-er,ythro-hex-2-enopyranoside to the corresponding cis glycol. Acidic hydrolysis of V l I I furnished a mixture of D-mannose, D-allose, and guanine as judged by paper chroniatography against authentic samples of D-mannose, nallose,25and guanine. The presence of D-mannose and D-allose in the hydrolysate of VI11 indicated that VI11 must be a mixture of 9-(D-manno-hexopyrariosyl)guanine and 9-(D-allo-hexopyranosyl)guanine+ These results firmly established the 2’,3’ position as the site of the endocyclic double bond in VII, and consequently in VI, 111,IV, and V. The nucleoside designated as 111 was successfully separated into two components (IV and V) by thick layer chromatography. Pmr techniques were employed to characterize IV and V (Table I). The sig nals at 6 5.44 in the 100-MHe pmr spectrum for IV and a t 6 5.50 in the 100-MHe pmr spectrum for 17 were assigned to H-4’. These assignments for H-4’ were made on the basis of the Rimilar chemical shifts observed for the signal a t 6 5.42 for I11 (which was established as H-4’ by decoupling from H-5’). The AB patterns for the protons in the 6 6.15-13.34 region for IV and in the 6 6.04-6.26 region for V were assigned to the C-2’ and C-3’ protons. The fine splitting seen in these patterns can be attributed to the additional coupling of the C-2’ and the C-3’ protons with H-1’ and H-4’. On the basis of these assignments, the downfield signals at 6 6.48 for IV and 6 6.60 for V were assigned to the anomeric protons. Ferrier13 has determined the anomeric configuration a t C-1 ’ of the corresponding 2,6-dichloro derivatives by analysis of the various coupling constants. The magnitudes of these couplings for the two anomers werc quite similar except for J 1 t - ~ ’ . The results of our analysis of anomers IV and V in CDC13 are generally in accord with those of Ferrier,I3though we consider other conformational possibilities. The J 1 t - - 2 t coupling for anomer IV was 2.8 Hz compared with 1.8 Hz for anomer V. Largc JV-Y values were found, 8.7 and 8.4 Hz, respectively, suggesting the half-chair H I conformation for the carbohvdrate moiety. However, the alternate h a l f - b ~ a t con~~~~~ ~ ? and cannot formation (Va) will also fit the J ~ J - data be readily eliminated, since the anomeric configuration is not known. I n the discussion below regarding the adenine analogs XVIII and XIX, the conformation and the a,P anomeric configuration dilemma were solved by synthesizing the Y 3 + C-6’ cyclonucleoside of the P anomer XIX. The spectra of XVIII and X I X with respect to the deblocked carbohydrate were essentially comparable to those of IV and V, and it is not expected that the conformation would change from H I for the adenine compounds to alternate half-boat for the 2-acetamido-6-chloro derivatives. On the basis of (24) C. L. Stevens, J. B. Fillipi, and K. G. Taylor, J . Org. Chem., 81, 1292 (1966).
(25) T h e authors wish to thank Dr. Bernice Kohn and Dr. Leon Lerner for a gift of n-allose. (26) K . A. Watanabe, R. S.Goody, and J. J. Fox, Tetrahedron, 26, 3883 (1970).
(27) W e acknowledge one of the referees for this suggestion.
3698
J. Org. Chem., Vol. 37, No. 23, 1972
SHUNAN, et al. TABLE I
C -h-em -cali-Compd
H-8
H-2
H-1’
H-2’
shifts, ppm H-3 ’
----------. H-4‘
H-5’
H-6‘,6”
IVn 8.18 6.48 6.15 6.34 5.44 -3.94 -4.16 Va 8.12 6.60 6.04 6.26 5.50 -4.2 -4.24 XVIIIb 8.61 8.61 6.82 6.44 6.67 4.45 3.91 3.91 XIXb 8.50 8.57 6.83 6.32 6.56 4.54 4.05 4.03 1x0 8.18 6.89 5.00 5.50 XI. 8.50 6.63 4.80 5.20 4.28 XIIC 8.33 6.75 4.88 5.23 4.00 XXb 8.49 8.49 6.94 5.10 5.47 4.62 4.27 4.12 XXIb 8.48 8.60 7.15 5.27 5.65 4.43 4.43 4.10 Spectra were determined in CDC18with TMS as internal standard a t 100 MHz on a Varian XL-100 spectrometer. Spectra were determined in DMSO-ds/DnOwith TMS as external standard a t 90 MHs on a Bruker HFX-90 spectrometer. Spectra were determined in DMSO-ds/D20 with TMS as internal standard a t 60 MHz on a Jeolco C60H spectrometer.
these considerations, I V and V were assigned the a and
mined by pmr studies in analogy to those reported by FerrieP for the 3’-substituted 2,6-dichloro derivatives. The formation of 9-( 1,5-anhydro-2,3-dideoxy-~-eryth- Large Jqt--jt (9.0 Hz) and J3,--?,(8.0 Hz) couplings sugro-hex-l-enitol-3-yl)-9H-purineshas been previously gest essentially diaxial orientations for H-3’, H-4’, and reported from the fusion of 3,4,6-tri-O-acetyl-~-glucal H-5’, which is consistent with the H1 conformation with purine^.^^^^^'^ The pmr spectra of the only other and pseudoequatorial orientation of thc substitucnt nucleoside IX isolated from the fusion of the ~-glucal at C-3’. Thus XI is 9-(1,5-anhydro-2,3-didcoxy-~(I) with 2-acetamido-6-chloropurine (11) was similar arabino-hex-1-enit 01-3-yl)-6-chloro-2-met hylthio-9Hto that of 6-chloro-9-(4,6-di-0-acetyl-1,5-anhydro-2,3purine and XI1 is the corresponding ribo derivative. dideoxy-~-arabino-hex-l-enitol-3-yl)-2-methylt hio-9HThe other nuclrosides XP showed absorption praks purine (XIII) and revealed a pair of doublets at 6 in the 6 5.9-6.3 region, which was characteristic for 6.S9 and a pair of overlapping doublets at 6 5.00, which H-2’ and H-3’ of a 2’,3’-unsaturated pyranosyl derivaare characteristic of a hex-1-enitol derivative, and which tive. On the basis of the similarities in the pmr spectra were assigned to H-1’ and H-2’, respectively. The in the region attributed to the carbohydrate moiety of doublet a t 6 5.50 in the pmr spectrum of IX was asXV and 111, this nucleoside was assigned the structurc, signed to H-3’ and the large coupling constant (J3t--?’= 6-chloro-9- (2,3-dideoxy-~-erythro-hrx-2-enopyranosy1)7.5 Hz) suggested that the 2-acetamido-6-chloropurinyl 2-methylthio-9H-purine. substituent was in approximately the same orientation Treatment of XV with methanolic ammonia in a as the 6-chloro-2-methylthiopurinyl substituent in sealed vessel at room temperature for 4 days furnished XIII. Thus, based on the similarities between the a 40% yield of 6-amino-9-(2,3-dideoxy-~-erythro-hex~ , 2-enopyranosyl)-2-methylthio-9H-purine pmr spectra of XI11 and IX and the largp J ~ F -oh(XVI). The served, the nucleoside IX was tentatively assigned the subsequent desulfurization of XVI with Raney nickel structure 2-acetamido-6-chloro-9- (4,6-di-O-acetyl-l,5furnished 9-(2,3-dideoxy-~-erythro-hex-2-e1lopyranosy1)anhydro-2,3-dideoxy-~-ara bino-hex-l-enitol-3-y1)-9Hadenine (XVII), mp 241-242’. A pmr spectrum of purine. XVII revealed an absorption pattern in the 6 5.8-6.2 The direct isolation and characterization of a minor region attributed to H-2’ and H-3’ of a 2’,3’-unnucleoside from certain transfer RNAs as a 2-methylsaturated pyranosyl derivative and indicated a retcnthiopurinc nucleoside d e r i v a t i ~ e ~ 8 $has ~ 9 created intion of the endocyclic double bond. The Synthesis terest in the synthesis of other 2-methylthiopurine nuof 9-(2,3-dideoxy-~-erythro-hex-2-enopyranosyl) adenine, cleosides. The fusion of 3,4,6-tri-O-acetyl-~-ghcal mp 241-242”, has been prcviously prrpared by a and 2-methylthio-6-chloropurine as reported in a predifferent procedure, although no attempt was made to liminary communication5 gave the three nucleosides establish the anomeric configuration of the XI, XII, and XV after treatment with methanolic I n fact, this structural assignment has been recently ammonia followed by fractional crystallization. questioned. l3 The assignment of the position of the endocyclic In view of the claimed antitumor activity of the double bond in XI and XI1 was previously firmly establatter p r o d ~ c t , 3a ~detailed investigation and synthesis lished by a comparison of the pmr spectra of XI and of the four possible isomeric adenine nucleosides XI1 with that of 3,4,6-tri-O-acetyl-~-glycal (I) (in XVIII, XIX, XX, and XXI was undertaken. The particular, J1t--2, 6 HZ was indicative of a vinyl fusion of 2,4,6-tri-O-acetyl-~-glucal (I) with 6-benzaether30) and by the utilization of the double resonance midopurine in the presence of p-toluenesulfonic acid technique at 100 RTHZ.~ Acetylation of XI and XI1 catalyst at 165’ for 3 hr gave a 76y0 yield of nut o XI11 and XIV caused a significant downfield shift of cleosidic material. Deacylation of the crude nucleothe C-4’ proton which was in agreement with the asside mixture with methanolic ammonia was followed by signment of purinyl substitution a t C-,7’.5 The conseparation of the nucleosides by column chromatogfiguration at C-3’ of XI and XI1 has now been deterraphy and fractional crystallization to give the isomeric nucleosides XVIII, XIX, XX, and XXI. A (28) s. M. Heoht, N . J. Leonard, W. J. Burrows, D. J. Armstrong, F.
P configurations, and HI conformations, respectively.
Skoog, and J. Occolowitz, Science, 166, 1272 (1969). (29) S. M. Hecht, L. H. Kirkegaard, and R. M. Bock, PTOC. Nat. Acad. S c i . U . S . , 68, 48 (1971). (30) R. J . Ferrier, A d u a n . Carbohyd. C h e m . , 24, 199 (1969).
(31) J . J. K. Novak and F. Sorm, Collect. Czech. C h e m . Commun., 27, 902 (1962). (32) J. ,J. K. Kovak and F. Sorm, Experientia, 17, 213 (1962).
UNSATURATED SUGARS IN NUCLEOSIDE SYNTHESES
J. Org. Chem., Vol. 37, No. 23, 1972 3699
c
XVII
comparison of the ultraviolet absorption spectra of these nucleosides with the ultraviolet spectra of the established N-9 as possible N-methyladeriine~~~’~~,~~ the site of glycosylation. The a and /3 anomers of 9-(2,3-dideoxy-~-erythro-hex2-enopyranosy1)adenine were identified readily due to the presence of the typical AB spin patterns for H-2’ and H-3’, with -10 Ha coupling. Large J 4 r - - 5 f couplings of 8-9 Hz for each isomer suggested diaxial arrangements of H-4’ and H-5’, consistent not only with H I , but also with the alternate half-boat.26 A largc J1!--2of 2.9 Hz was observed for XVIII, whereas for XIX the coupling was about 1.5 Examination of models revealed that an a anomer in the HI conformation and a p anomer in the alternate half-boat (Va) were both consistent with diaxial H-4’ and H-5’ and equatorial-vinylic H-1’ and H-2’, the latter arrangement leading t o an expected vicinal J ~ t - ~ oft about 3 Hz (in an axial-vinylic case the J1,--2, would be about 1.5 Hz).30 At this point it was not possible to proceed with an assignment based upon pmr, since both conformation and anomeric configuration were unknown. Thus, a chemical assignment was attempted. Further study of Drieding’s models showed that in the case of the p anomcr it might be possible to form a N3+ C-6’ cyclonucleoside ; however, N3+ C-6 ’-cyclonucleoside formation from the a anomer would be difficult, if not impossible, no matter what the carbohydrate conformation because of distance considerations. Accordingly, the 6’-O-tosyl derivatives of both XVIII and XIX w r e synthesized by treatment with p-toluenesulfonyl chloride in pyridine-chloroform, Selective toeylation at the 6’ position was shown in the pmr spectra in DAISO-& by the absence of the 6’-OH (triplet signal 6 *5,09PPm from TXS-capillary). KpOn heating, the tosylatcd XIX reacted to form the N3 + (33) R . I220" dec; uv' , :A: (E 11,500), 275 (8200); ' : : :A 262 nm (E 12,000). resulting solution was allowed to cool at room temperature for 2 days in a closed vessel. The crystalline solid which had separated Anal. Calcd for CllH1~N504~1.50H~O: C, 43.13; H, 5.26; was collected by filtration to yield 120 mg of an analytically pure N, 22.86. Found: C, 42.75; H, 5.19; N, 22.58. : : :A 229 nm ( E 2:,500), 260 sample of I X : mp 104-105'; uv The pmr spectrum of VI1 revealed an absorption peak a t S 4.0 which integrated for three protons and was assigned to the 1.5 231 nm (e 24,000), 260 (9700), 285 (9700), 285 (11,100);' : : :A mol of water. (11,100);" : : :A 230 nm (e 26,100), 257 (9500), 288 (11,100). 9-(D-manno,D-allo-Hexopyran0syl)guanine (VIIIj .-9- (2,3Anal. Calcd for C ~ ~ H & ~ ~ SC, O 48.17; B: H, 4.25; N , 16.53. Dideoxy-~-erythro-hex-2-enopyranosyl)guanine(VII) (50 mg, Found: C, 48.21; H , 4.40; X, 16.15. 0.16 mmol) was dissolved in a 1 : 1mixture of water and tert-butyl 9-(1,5-Anhydr0-2,3-dideoxy-~~arabzno-hex-l -enitol-d-yl)-tjalcohol (10 ml) and to this solution was added 0.5 mg (0.002 chloro-2-methylthio-9H-purine (XI) and 9-( 1,5-Anhydro-2,3-dimmol) of osmium tetroxide and 1 ml of 30% hydrogen peroxide. -enitol-3-yl)-6-chloro-2-methylt hio-9H-purine deoxy-~-ribo-hex-l The solution was allowed to stand a t room temperature for 2 (XII).--A finely powdered mixture of 6-chloro-2-methylthiodays, after which the excess hydrogen peroxide was decomposed (I) purine4? (X) (10 g, 50 mmol) and 3,4,6-tri-0-acetyl-~-glucal by the addition of a small amount of platinum black. The mix(20 g, 73 mmol) was heated to an inside temperature of 120" in ture was filtered through a 4-mm-thick Celite bed, the Celite bed an oil bath. To the hot mixture was added, with thorough mixwas washed with 20 ml of hot water, and the combined filtrates ing, 50 mg of p-toluenesulfonic acid and heating was continued were evaporated to a residue under high vacuum a t room tema t 120" (inside temperature) under aspirator vacuum for 2 . j hr. perature. The residue was recrystallized from water (3 ml) to The dark melt was dissolved in warm ethyl acetate (900 ml), the 253 nm (E lO,OOO), furnish 6 mg of VIII: mp >160' dec; uv A:i insoluble material was removed by filtration, and the filtrate was 275 (7000); 263 nm (e 10,000). cooled to 0". The filtrate was washed with cold saturated sodium Anal. Calcd for CI~HI~NSOB: C, 42.17; H , 4.79; N , 22.36. bicarbonate solution (3 X 200 ml) and cold water (3 X 200 ml) Found: C, 42.21; H , 4.83; N, 22.50. and then dried over anhydrous sodium sulfate. The sodium Hydrolysis of 9-(D-manno,D-allo-Hexopyranosyl)guanine(VI11 ). sulfate was removed by filtration and the filtrate was concentrated -9-(D-manno,D-abHexopyranosyl)guanine (VIII) (50 mg, to 500 ml. Silica gel (J. T. Baker powder, 40 g), Celite (Johns 0.16 mmol) was dissolved in 5 ml of water. To this solution was Manville, 20 g) and 0.057, by weight of phosphor (Du Pont added 10 g of Amberlite IR-120resin (H+form) and the mixture # 609) was added to the ethyl acetate solution and the resulting was allowed to stand a t room temperature for 24 hr. The resin mixture was evaporated under high vacuum and at room temwas then removed by filtration and washed with 50 ml of water perature to a dry powder. This powder was placed on top of a a t room temperature. The filtrates were combined and concenpreformed nylon dry column (1.75 x 13 in.) of Baker silica gel trated to 1 ml under high vacuum at room temperature. An powder containing 0.05% by weight of phosphor. The column ultraviolet absorption spectrum and a positive Fehling's test inwas eluted with 2 1. of a n-pentane-ethyl acetate (9: 1, v/v) soldicated that hydrolysis had occurred. The hydrolysate was vent system and the eluent was discarded. The nucleoside band applied to Whatman S o . 1 chromatography paper, and the paper near the top of the column (dark band under ultraviolet light, was developed by the descending technique with a cyclohexane254 nm) was excised and triturated with 1 1. of warm absolute pyridine-water (40:23: 19.5, v/v/vj solvent system,*s air dried, ethyl alcohol, and the silica gel was removed by filtration. The and then sprayed with a silver nitrate spray reagent.46 A final filtrate was concentrated to a stiff foam under high vacuum a t spray with ethanolic sodium hydr'oxide solution revealed two 60". This foam was dissolved a t room temperature in absolute components (detected as black spots) present in the hydrolysate. methyl alcohol (250 ml) and then cooled to -20". The cold These two components were identified as D-mannose and D-allose solution was saturated with ammonia and then allowed to stand values (1.45 and 1.25, respecby comparison of the Rga~natose at -20" for 12 hr. Excess ammonia and solvent was removed at tively) with those observed for authentic n-mannose (1.45) and room temperature under aspirator vacuum to afford a syrup. D-allose (1.25),25 The syrup was dissolved a t room temperature in absolute metha2-Acetamido-6-chloro-9-(4,6-di-0-acetyl-~,3-dideoxy-~and nol (500 ml) and the resulting solution was allowed to stand a t -P-~-erythro-hex-2-enopyranosyl)-PH-purine (IV and V ) .-2-Acetroom temperature for 2 days. The crystalline solid which had amido-6-chloro-9-(4,6-di-0-acetyl-2,3-dideoxy-~-erythro-hex-2separated was collected by filtration to furnish 1.77 g of X I , mp 196-198'. Recrystallization from absolute methanol furnished (45) H . Ruokert, E. Pfeil, and C. Sharf, Chem. Ber., 00, 2558 (1965). 1.24 g of XI: mp 214-215'; uv 236 nni (e 11,000), 260 (46) L. Hough and J . K. N . Jones in "Methods in Carbohydrate Chemistry," Vol. 1, Academic Press, New York, N . Y., 1962, p 21; L. Hough, Nature (London), 166, 400 (1950).
(47) C. Wayne Noell and R. K. Robins, J .
O w .Chem., 24,320 (1959).
3702 J . Org. Chem., Vol. $7, N o . $3, 1972
SHUMAN, et al.
(7200), 305 (5300);' : : :A 238.5 nm (e 12,800), 260 (7900), 305 mixture was sealed in a pressure bottle and allowed to stand a t (6200); A% 236 nm (E 14,100), 260 (SSOO), 305 (6900). room temperature for 3 days. Excess ammonia and solvent were Anal. Calcd for C I Z H ~ ~ C I N ~ O C,~43.84; S: H,3.98; jN, 17.04. removed under aspirator vacuum and the residue was then tritFound: C, 43.96; H , 4.12; N, 16.98. urated with four portions of 150 ml each of anhydrous ether. The filtrate from above was concentrated to 100 ml and alThe remaining solid was slurried in 10 ml of hot absolute ethyl lowed to stand a t room temperature for 72 hr. The crystals alcohol and cooled to room temperature, and the solid was which had formed were collected by filtration to yield 1.36 g of collected by filtration to yield 116 mg (62%) of product, mp 196XV, mp 170-174". 198". Recrystallization from 5 ml of ethyl alcohol-water (9 : 1, v / v ) furnished 49 mg of pure 6-amin0-9-(2,3-dideoxy-nThe above filtrate was then concentrated to 50 ml. After 1 week in a closed vessel a t room temperature there was obtained erythro-hex-2-eno yranosyl)-2-methylthio-9H-purine (XVI): mp €? 269 nm (e 13,000);' : : ;A 235 nm ( e 17,300), 236-237'; uv AEaX1 1.81 g of X I I , mp 149-157'. Recrystallization from absolute methanol furnished 827 mg of an analytically pure sample of 275 (13,000); A?: 260 nm (E 17,600). X I I : mp 177-178'; uv Af,' 237.5 nm ( E 18,000), 261 (10,200), Anal. Calcd for C1zH15N503S:C, 46.60; H, 4.85; N, 22.65. 236 nm ( e 29,200), 261 (11,300), 305 (8200); Found: C, 46.69; H , 4.87; N, 22.68. 306 (7700); ';:A: A% 237.5 nm ( e 18,000), 261 (9500), 305 (8200). 9- (2,3-Dideoxy-n-erythro-hex-2-enopyranosyl)adenhe(XVII) 6-Amino-9-(2,3-dideoxy-n-ery~hro-hex-2-enopyranosyl)-2-methylAnal. Found: C, 43.84; H, 4.00; N, 17.20. thio-9H-purine (XVI) (80 mg, 0.26 mmol) was dissolved in 80 ml of 6-Chloro-9-(4,6-di-O-acetyl-l ,5-anhydro-2 ,3-dideoxy-u-arabinowater, 400 mg of W-4 Raney nicke14*was added, and the mixture hex-l-enitol-3-yl)-2-methylthio-9H-purine (XIII) and 6-Chloro-9(4,6-di-O-acetyl-l,S-anhydro-2,3-did eoxy-~-ribo-hex-l-enitol-3- was heated at reflux temperature for 3 hr. An additional 400 mg of Raney nickel was then added and the mixture was allowed to yl)-Z-methylthio-9H-purine (XIV).-To 25 ml of acetic anhydride stand at room temperature for 16 hr. The Raney nickel was and pyridine (1:4, v/v) was added 230 mg (0.70 mmol) of X I removed by filtration through a 3-mm-thick Celite bed, the Celite and the mixture was allowed to stand a t room temperature for bed was washed with 50 ml of hot water, and the combined 12 hi with frequent shaking. The resulting solution was poured filtrates were evaporated to dryness under high vacuum and into 150 ml of crushed ice and stirred thoroughly for 15 min. room temperature. Ultraviolet spectral analysis revealed that This mixture was extracted with CHCL (2 X 100 ml), the chlorothe 2-methylthio group had been removed. crystallization from form fractions were combined and washed with cold (0') 1 X HCl water furnished 12 mg of an analytically pure sample of 9-(2,3solution (3 X 200 ml) and cold (0') saturated sodium bicarbonate dideoxy-n-erythro-hex-2-enopyranosy1)adenine(XVII) : mp 241solution (3 X 200 ml), and the chloroform solution was then 257 nm (E 14,700);' : : :A 260 nm (e 15,600);: : A 242"; uv' ,:A; dried over anhydrous sodium sulfate. The sodium sulfate was 259.5 nm ( e 15,300). removed by filtration and the chloroform filtrate was concenAnal. Calcd for C11H13N603: C, 50.19; H , 4.95; N, 26.62. trated to 10 ml volume and applied to the top of a dry-packed Found: C, 49.99; H, 4.90; N, 26.78. column of Baker silica gel powder (12 X 0.5 in.). The column 9-(2,3-Dideoxy-~-n-e~ythro-hex-2-enopyranosyl)aden~ne (XIX) was eluted with ethyl acetate (500 ml) and the eluent was and 9-(2,3-Dideoxy-~~n-erythre-hex-2-enop y r a n o s y 1)ad e n i n e evaporated under high vacuum and a t room temperature to (XVIII).-A finely powdered mixture of B-ben~amidopurine~~ afford a stiff syrup. This syrup was dissolved in 2 nil of anhy(20.0 g, 84 mmol) and I (46.5 g, 0.171 mol) was heated in an oil drous ether and allowed to stand a t - 10" for 24 hr. The crystals bath (165") until a melt was formed. To the melt was added which had separated were collected by filtration to yield 40 mg of p-toluenesulfonic acid monohydrate (100 mg) and the heating analytically pure X I I I : mp 117-118'; uv Ak!,ft.' 237 nm (t was continued under aspirator vacuum for 3 hr. The melt was 18,100), 260 (10,600), 305 (8400);' : : :A 238 nm ( E 16,700), 260 poured into 500 ml of ethyl acetate and washed twice with water. (10,600), 304 (8800); :?A 237.5 nm (e 20,400), 260 (11,900), The ethyl acetate layer was dried over magnesium sulfate, 305 (9800). filtered, concentrated to a small volume, and applied to a silicic Anal. Calcd for CleH17C1N405S: C, 46.54; H , 4.12; N, acid column (J. T. Raker, No. 3405; 18 X 2.5 in.). The 13.58. Found: C, 46.47; H , 4.18; N, 13.43. colunin was washed with petroleum ether (bp 30-60')-chloroThe same procedure as above was followed except that 260 mg form (1:4, v/v) to remove glucal and then chloroform to remove (0.791 mmol) of XI1 was used instead of 250 mg. The dry column nucleosidic material (64 mmol). The nucleosidic material was was eluted with ethyl acetate (700 ml) and the eluent was condissolved in 750 ml of methanol saturated with ammonia a t 0' centrated to a 5-ml volume. This solution was applied to two and set at room temperature for 3 days. Concentration of the preparative layer SilicAR 7GF chromatography plates (7.75 X methanolic solution gave 7.9 g of crystalline material, mp 21215.75 in., 2 mm thickness). The plates were developed the full 214'. A ZOO-mg portion of this was preabsorbed on 15 g of length (14 in., measured from the base line) in an ether-petroleum Mallinckrodt SilicAR CC7 (200-325 mesh) and applied to a ether (bp 60-90') (9:1, v/v) solvent system. The band was SilicAR CC7 column (15 X 1.25 in., packed in chloroform). removed and extracted with 200 ml of warm absolute ethanol. The column was successively washed with 2 1. of methanolThe ethanol solution was evaporated under high vacuum and a t dichloromethane (5395, v/v) and 2 1. of methanol-dichlororoom temperature to a syrup. This syrup was dissolved in 5 ml methane (6: 94, v/v), followed by methanol-dichloromethane of water-methanol (9:1, v/v) and the resulting solution was (7:93, v/v). The first main frartion was evaporated and the hylized to yield 40 mg of analytically pure XIV: mp 72-73"; residue was crystallized from ethanol to give a mixture of XX and 238 v:$: 236.6 nm ( e 18,200), 261 (9800), 305 (7800); ':A$: X X I (0.14 g). The second main fraction after evaporation and nm (e 16,300), 261 (9600), 305 (7800); 237 nm ( e 19,100), crystallization from ethanol gave 0.16 g of pure XVIII: mp 261 (lO,OOO), 306 (8700). 257 nm (t 15,500);' : : ;A 260 nm ( e 243-245' dec; uv: : :A Anal. Calcd for ClaH1~CINIO,S~H~O: C, 44.60; H, 4.41; N , 16,200); 260 nm ( E 16,000). 13.01. Found: C, 44.98; H , 4.24; N, 12.97. Anal. Calcd for C1,H19N6OI: C , 50.19; H, 4.94; N, 26.62. A pmr spectrum of XIV in DMSO-& showed a water peak a t Found: C, 50.19; Hi-4.93; K, 26.80, 6 4.0 which integrated for two protons or one molecule of water. The filtrate which was obtained from the filtration of the 6-Chloro-9-(2,3-dideoxy-~-erythro-hex-2-enopyranosyl)-2-meth-nucleosidic material, mp 212-214", in the above preparation was ylthio-9H-purine (XV) .-The filtrate from the acid-catalyzed concentrated and applied to a silicic acid column (J. T. Baker fusion of 3,4,6-tri-0-acetyl-n-glucal with 6-chloro-2-methylthioKO.3405; 10 X 2.5 in.). Elution of the column nTith methanolpurine was reported to furnish a crude nucleoside with mp 170chloroform (8:92, v/v) removed 7 g of nucleosidic material. 174". Recrystallization of this product from absolute methanol Fractional crystallization of the nucleosidic material from ethanol gave I .03 g of analytically pure 6-chloro-9-(2,3-dideoxy-n- concentrated X I X in the filtrates. The filtrate was evaporated erythre-hex-2-enop~~ranos~rl)-2-methyllhio-9H-purine (XV): mp and the residue (5.8 g) was dissolved in water and applied to a 260 nm (e 11,800), 305 (7200);' : : A: 234 nm 184-185'; uv' .:A: Dowex AG 1x8 200400 mesh column (OH form; 20 X 5.5 in.). ( e 19,100), 263.5 (11,500), 305 (7600); A% 233 nm (E 18,400), Elution with 50% aqueous methanol gave, after evaporation and 263 (11,800), 305 (7800). crystallization of the appropriate fractions, 1.4 g of X I X : mp Anal. Calcd for C1~H13Clr\T103S:C, 43.84; H, 3.98; PI', 195-1963' (resolidifies, mp 210-215'); uv 257 nm ( e 17.04. Found: C, 43.75; H , 4.15; N, 17.34. 15,000);' ::A: 259 nm (E 16,000); 259 nm ( E 15,600). 6-Aniino-Q-(2,3-dideoxy-n-erythre-hex-2-enopyranosyl)-2-methylthio-9H-purine (XVI).-To 40 ml of inethanolic ammonia was added 200 nig (0.608 mmol) of 6-chloro-9-(2,3-dideoxy-n(48) Purchased from W. R. Grace and Co. erylhro-hex-2-enopyranosyl)-2-methylthio-9H-pur~ne (XV). This (49) A. Kossel, Z. Physiol. Chem., 12, 241 (1888).
.-
70
METHYL 3-0-ACETYL-2,3-DIHYDROXY-2-METHYLPROPANOATE
J . Org. Chem., Vol. 37, No. 23, IQY2 3703
Anal. Found: C, 49.98; H, 4.97; N,26.56. XXIII: mp 218.5-219.5' dec; uv: : A: 256 nm (e 11,800);' ::A: 9-( 1,5-Anhydro-Z,3-dideoxy-D-arahino-hex1-enitol-3-y1)adenine 258 nm (e 12,300); ::A: 258 nin ( E 12,200). (XX) and 9-(1,5-Anhydro-2,3-dideoxy-n-ribo-hex-l-enitol-3-yl)- Anal. Calcd for CnH151T50s:C, 49.80; H, 5.69; N, 26.40. adenine (XXI).-A mixture of X X and X X I (1.6 g) obtained as Found: C, 49.77; H,5.49; ?J, 26.55. described in the preparation of XVIII was applied to a Dowex 9-( 1,5-Anhydro-2,3-dideoxy-~-arahino-hexitol-3-yl)adenine AG 1 x 8 200-400 mesh column (OHform; 19 X 5.5 in.). Elu(XXII).-Hydrogenation of 9-(1,5-anhydr0-2,3-dideoxy-n-aration of the column with 50% aqueous methanol gave after conbino-hex-1-enitol-3-y1)adenine(XX) (200 mg, 0.8 mmol) as in centration and crystallization from ethanol 0.67 g of XXI, mp the procedure for XIV gave after cr stallization from ethanol 120 ' : : :A 260 nm (e 15,600), 219-220, uv A%: 258 nm (e 15,200), 257 nm (e 14,400); ' : : :A 260 mg of XXII: mp 233-235'; uv' {:A " : :A 260 nm (E l5,400), and 0.69 g of XX, mp 198-201°, uv 260 nm (e 14,700). nm (e 14,700);$ :A : : :A 268 nm (t 15,200), ' : ! :A 260 nm (e 15,600), " : :A 260 nm Anal. Calcd for CllH15N603~1/4HpO: C, 48.17; H, 5.88; N, (e 15,400). 25.53. Found: C, 48.15; N, 5.60; N,25.73. Anal. Found for XXI: C, 50.20; H , 5.00; N, 26.49. Found for X X : C, 49.95; H, 5.03; IT, 26.63. Registry No.-111, 20757-44-4; IV, 35667-23-3; V, 9-(2,3-Dideoxy-cr-~-erythro-hexopyranosyl)adenosine(XXIV) 35667-24-4; VI, 35667-25-5; VII, 20789-65-8; VI11 9-(2,3-Dideoxy-a-n-erythro-hex-2-enopyranosyl)aden~ne (XVIII) (manno), 35667-27-7; VI11 (allo), 35667-28-8; I X , (200 mg, 0.8 mmol) was dissolved in 50 ml of water. To this 35666-84-3; X I , 30624-97-6; X I I , 31654-90-7; X I I I , solution was added 100 mg of lOy0 Pd/C and the mixture was then shaken with hydrogen a t 45 psi and room temperature for 8 35666-86-5; XIV, 35666-87-6; XV, 35667-29-9; XVT, hr. The Pd/C was removed by filtration through a Celite bed, 35667-30-2; XVII, 35667-31-3; XVIII, 35666-83-2; the Celite bed was washed with 50 in1 of hot water, and the comXIX, 35737-21-4; XXI, 35657-25-1; X X I I , 35657bined filtrates were evaporated in vacuo to a residue. The residue 26-2 X X I I I , 35657-27-3 ; XXIV, 35657-28-4; 2was crystallized from ethanol-water to give 100 mg of XXIV: acetamido-6-chloropurine, 7602-01-9. : : :A 257 nm (e 14,300); ' : : :A 260 nm (e 14,900); mp 236-237'; uv 260 nm (e 15,700). Anal. Calod for CilH1~N603:C, 49.80; H, 5.69; N, 26.40. Acknowledgment.-The authors wish to thank Dr. Found: C, 49.62; H, 5.61; N,26.56. G. D. Daves and Mr. W. Anderson for the decoupled 9-(2,3-Dideoxy-p-~-erythro-hexopyranosyl)adenine (XXIII).1OO-MI1z pmr spectra, Ah-. E. B. Banta for the 90-MHe Hydrogenation of 9-(2,3-dideoxy-p-~-erythro-hex-2-enopyranopmr spectra, and I l r . A. F. Lewis and staff for the sy1)adenine ( X I X ) (100 mg, 0.4 mmol) for 6 hr as in the procedure large-scale preparation of intermediates. for XXIV gave after crystallization from ethanol 60 mg of
.-
The Absolute Configuration of Methyl 3-0-Acetyl-2,3-dihydroxy-2-methylpropanoate by Nuclear Magnetic Resonance and Chemical Determination
FREDL. SHORE^
AND GEORGEU. YUEN"
Department of Chemistry, Arizona State University, Tempe, Arizona 86881 Received April 18, 1972 The chemical transformation of (A')-( +)-atrolactic acid to methyl 3-O-acetyl-(R)-2,3-dihydroxy-2-methylpropanoate (I), [crIz3~ -9.5', gives an absolute configuration in agreement with the prediction from solvate models and the sense of nonequivalence apparent in the nmr spectra of 1 in the solvent (E)-1-(1'-naphthy1)ethylamine.
A study of the Grignard reaction with optically a. a' d a,a' b CH,-O-COCHj CHz-OH active carbonyl compounds, being carried out in this m 1 - b m l b laboratory, yields products of unknown stereochemHjC-C-OH H&-C-OH istry, whose absolute configuration can be determined I C I P most conveniently by degradation to an enantiomer Ph CO,CH of a-methylglyceric acid. The resolution of a-methyl1 ( S ) isomer 2 ( R )isomer glyceric acid (2,3-dihydroxy-2-methylpropanoicacid) b P I d was attempted without success by Glattfield and Sher~H2-O-COCH(OH)Ph CH2-O-COCH, man.2 Preparation and assignment of the absolute 111 I b m l b configuration of methyl 3-0-acetyl-2,3-dihydroxy-2- H,$--Q-OH H,C-C-OH methylpropanoate (1) (Table I) is described herein. I P I P Ph Ph Two methods of assignment were used: chemical 3 4 transformation of (8)-(+)-atrolactic acid of known absolute configuration3 to methyl 3-0-acetyl-(22)-2,3a b a U CHz-OH CH2-OCOPh dihydroxy-2-methylpropanoate, viu reactions remote from the asymmetric center; and establishment of a consistent pattern between the sense of nonequivalence apparent in the nmr spectra of methyl 3-0acetyl-(R)-2,3-dihydroxy-2-methylpropanoateand its 5 6 enantiomer in the solvent (R)-1-(1'-naphthy1)ethylamine with predictions based on solvate models. and Freeman4 and partially resolved as the quinine Atrolactic acid was prepared by the method of Eliel salt using the procedure of McKenzie and C l ~ u g h . ~ The partially resolved (8)-atrolactic acid was then (1) Taken from the Ph.D. Dissertation of Fred L.Shore. reduced by lithium aluminum hydride to (8)-(+)~
(2) J. W. E . Glattfeld and
L. P. Sherman, J. Amer. Chem. Soc,, 47,
(1925). (3) J . H. Brewster, ibid., 78, 4061 (1956).
1742
(4) E. L. Eliel and J. P. Freeman, O r g . Sun., 53, 7 (1953). ( 5 ) A. McKenzie and G. 7V. Clough,J. Chem. Soc., 97, 1016 (1910)
